Cardiac glycosides

ABSTRACT

Compounds of the formula   WHEREIN R is cyano or carbalkoxy of 2 to 4 carbon atoms; the compounds are useful as cardiotonics.

United States Patent Eberlein et al.

1 5: Sept. 23, 1975 CARDIAC GLYCOSIDES Inventors; Wolfgang Ebcrlcin Mcucnhcrg;

Joachim lleidcr, Warthuuscn-()hcrhul'cn; Willi Die-damn, Risscgg, all of Gcrnmny; Waller Kobingcr, Vicnna, Austria Assigncc:

Bnehringcr lngelhoim (llnhH,

lngclhcim um Rhine, (icrmzmy Filed:

Sept. l7, I973 Appl. No: 597,852

Foreign Application Priority Data Sept. 18, 1972 Germany .7 2245726 US. Cl .7 260/2105; 4Z4/l 82 Int. Cl. (.071 5/00 Field of Search ZOO/2W5 [56] References (filed UNll'lil) S'lA'llES PAI'EN'IS 3.5 l4,44l 5/1970 Samh cl ul .4 260/2 lUS 17523403 X/l973 liberlcin cl all 260/2l05 Primary Examiner -Juhnnic R. Brown Assislun! lz'xumim'r(fary B. ()wcns Almrney, Agenl, or I"irmHumm0nd & Litlcll l l ABSTRACT Compounds of the formula HO cn= wherein R is cyunu or czirbulkuxy of 2 to 4 carbon atoms; the compounds are useful as curdimonics.

4 Claims, N0 Drawings CARDIAC GLYLOSllJliIS- point of the solvent medium. This invention relates to novel cardiac glycosides, as The starting compounds of the formulas ll and III at well as to a method of preparing these compounds. described in the literature (see Belgian Pat. N(

More particularly, the present invention relates to :a 774,509 and U.S. Pat. No 3,752,803). For instance, novel class of cardiac glycosides represented by the for compound of the formula II is obtained by reacting 3p mula I (tridigitoxosyLtetraacetate IZB-acetoxy- 1 4B- wherein R is cyano or carbalkoxy of 2 to 4 carbon hydroxy-l7B-formyLSB-androstane with diethylpho:

atoms, preferably methoxycarbonyl. phono-acetonitrile or the corresponding diethylphos The om nd emb ed b f mul I may be r phonoacetie acid ester in the presence of a base, sue; pared by reacting a compound of the forntula f as potassium tert.butylate, and subsequently removin CH3 H3 H3 H H OH H wherein R has the satne meanings as in formula I, with the four protective acet'yl substituents.

a Compound f i f m la The following examples further illustrate the presen invention and will enable others skilled in the art to un u derstand it more completely. It should be understood ll however, that the invention is not limited solely to th x c x a (lll) particular examples given below,

wherein X is halogen, imidazolidyl, lower alkoxy, aryl- EXAMPLE 1 lower alkoxy or aryloxy, in an inert organic solvent, such as ether, dioxane. tetrahydrofuran, methylene chloride, dichloroethane or dimethylformamide, and

optionally in the presence of a tertiary organic base, 1 such as triethylamine or pyridin A solution of L5 gm (l.9 millimols) of 3-(3'B When X in formula lll is halogen, the reaction ispreftridigitoxosyll Z'fi,l4B-dihydroxy-5'B-androstan erably performed in the presence of a tertiary organic l7'B-y|)-aerylonitrile in 75 ml of pyridine was ZldIfllXC base, such as triethylamine or pyridine; if the tertiary dropwise with 18 mlo'f a 10 percent solution of phos organic base is a liquid at the reaction temperature and ne in toluene,- ,wltile' cooling the mixture on an ic is provided in sufficient excess, it may simultaneously h m, flh resulting mixture was stirred for one hou serve as the solvent medium for the reaction, The reaev. mo t 0C and was then poured into 200 ml of ice wa tant ofthe formula lll is advantageously provided in exwr The r lting a ueou mi t nwd Sev cess over the stoichiometrically required amount. The ra] times withchloroform, and the combined organit reaction temperature may vary between 60C and the v t were washed successively with dilute hydro boiling point of the particular solvent medium which i ehloric acid, a saturated. aqueous sodium bicarbonatt used. but the reaction is preferably performed at a temsolution and water, dried over sodium sulfate and evap perature between 20 and -l-20"Cw orated to dryness in a rotary evaporator. The rcsidu: When X in formula III is imidazolidylfthe reaction is, was chromatographed on 200 gm of activated silicage preferably carried out with one mol-equivalent of a with chloroform/acetone (ozl to 2:1), yielding 53( compound of the formula lll and within the temperamgm (25.6 percent of theory) of the compound of thc ture range of 0 and l00(., preferably at the boiling formula CH CH which had a melting point of ()-252( after being androstan-l7fi-yl)-acrylonitrile 3",4-carbonate recrystallized twice from chloroform/cyclohexane. (A) according to the present invention in comparison R Value: 0.45 (flow agentzethyl acetate) to the prior art precursor 3-(3B-tridigitoxosyllR-Bands (solid in KBr) 3400-3550 cm" (-OH). iZB l4B-dihydroxy-5'B-androstan-l7B-yl)- 2230 cm (-CN acrylonitrile (B) was ascertained by the following tests:

I810 cm (carbonate),

I625 cm (-C=( l. Infusion toxicity in cats:

EXAMPLE 2 The compound under investigation was intravenously Using a procedure analogous to that described in Exinfused into cuts of 2-3 kg body weight under pentoample l, 620 mgm percent of theory) of pure barhital anesthesia (30 mgm/kg i.v.), while administermethyl 3-(3'B-tridigitoxosyl-l2B,l4B-dihydroxy-5'B- ing artificial respiration [see R. A. Hatcher et al., Am.

androstan-l7'B-yI)-acrylate 3"',4"-carbonate, nip. 1. Pharmac. 82, 360 (l9lt))]. The infusion rate was 225-227C (recrystallized from chloroformleyclohexchosen to be such that death due to heart failure ocane), of the formula curred after 50 to (ill minutes and front the raw data were obtained from l.5 gm (L9 millilmols) of methyl the average absolute lethal dose (LD was calcu- 3-(3B-tridigitoxosyl-l2'B,l4'l3-dihydroxy-5l3- lated. The following table shows the results obtained. androstan-l7B-yl)-acrylate and 18 ml of a It) percent H solution of phosgene in toluene. ABM:

R Valu'e: 0.45 (flow agentzethyl acetate) B (solid in KBr )2 355() 32UU cm I ()H Compound Number of animals Ll)... mgm/kg iv.

I810 cm" (carbonate lnvcmhm I715 cm (ester A :4 31s m, t Prior art: 1630 em B y 4 52s The compounds embraced by formula I have useful pharrnacodynamic properties. More mrticularly they 55 exhibit cardiotonic and especially positive inotropic activities in warm-blooded animals, such' as cats and Emmi" bsmpnonmm in guinea pigs; The compounds of the present invention I Th m r l b or tion r te was determined for each are further characterized by a very favorable oral abt t compound by way of the K'-elimination in he sorption rate, as well as by a very favorable rate otelimurine f rats b d mini those doses which, after ination which corresponds to that of g stroplumthin, intravenous dmini tion, roduced the same K*- whereby the danger of cuinulation and occurrence of elimination as after peroral administration within a perintoxication symptoms is reduced. iod of two hours [see Arch. Path. and Pharmakol. 233. For instance, the more favorable absorption rate of 468 lX)]. The following-table shows the results ob.

l'ABLli ll Compound lznlcral absorption rate attcr 2 hours Jnyegtxon; I:

Frtor an.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals perorally or parenterally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective dosage unit of the compounds according to the present invention is from 0.002 to 0.034 mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 3 Tablets Thetablet composition is compounded from the following ingredients:

3",,4"-carbo|tate 0.25 parts Lactose 85.75 Potato starch 30.00 Lielatain 3.00 Magnesium stearate L00 Total 120.00 parts is dried at 40C and again passed through a l mm-mesh screen, the dry granulate is admixed with the magnesium stearate, and the composition is compressed into 120 mgm-tablets in a conventional tablet making machine. Each tablet contains 0.25 mgm of the acrylonitrile compound and is an oral dosage unit composition with effective positive inotropic cardiotonic action.

EXAMPLE 4 Coated pills The pill core composition is compounded from the following ingredients:

3"'.4"'-carbonate 02s path Lactose 32.25 (om starch 15.00 Polyvinylpyrrolidone 2.00 Magnesium stcarate 0 S0 I'oial 50.00 parts Preparation:

The acrylonitrile compound is intimately admixed with 2.5 parts of lactose, the mixture is admixed with the remainder of the lactose and the corn starch, the resulting mixture is moistened with an aqueous l5 per cent solution of the polyvinylpyrrolidone, the moist mass is forced through a l rum-mesh screen, the resulting granulate is dried at 40C and again passed through the screen, the dry granulate is admixed with the magnesium stearate, and the composition is compressed into 50 mgm-pill cores which are subsequently coated with a thin shell consisting essentially of a mixture of sugar and talcum and polished with beeswax. Each coated pill contains 0.25 mgm of the acrylonitrile compound and is an oral dosage unit composition with effective positive inotropic cardiotonic action.

EXAMPLE 5 Drop Solution The solution is compounded from the following ingredicnts:

3-( 3 'B-Tridigitoxosyk l 4 'BJtydroxy-S 'fiandrostanl 7'B-yl l-acrylonitrile 3",4"'-carbonate 0.0l25 parts Saccharin sodium 0.3

Sorbic acid (H Ethanol 30.0

Flavoring Lo 4:

distilled water q.s.ad l00.0

Preparation:

EXAM PLE 6 Hypode rm ic solution The solution is compounded from the following ingredients:

3".4"'-carhonate 0.25 parts Polyethylencglycol 600 l50.00 Tartaric acid 5.00 Distilled water q sad l000.00

by vol.

Preparation:

The tartaric acid, the polyethyleneglycol and the acrylonitrile compound are successively dissolved in a sufficient amount of distilled water, and the resulting solution is diluted to the indicated volume with distilled water and then filtered until free from suspended matter. T'M "JJate is fillu' nto nil-ampules an atm0- sphere of nitrogen, and the tilled ampules are sterilized for minutes at 120C and then sealed. Each ampule contains 0.25 mgm of the acrylonitrile compound, and the contents thereof are an injectable dosage unit composition with effective positive inotropic cardiotonic action.

EXAMPLE 7 Suppositories The suppository composition is compounded from the following ingredients:

Preparation:

The acrylonitrile compound and the lactose are admixed with each other, the mixture is milled and then blended with the aid of an immersion homogenizer in the suppository base which had previously been melted and cooled to 40C, and I700 mgm-portions of the resulting composition are poured at 37C into cooled suppository molds and allowed to harden. Each suppository contains 0.25 mgm of the acrylonitrile compound and is a rectal dosage unit Composition with effective positive inotropic cardiotonic action.

Analogous results are obtained when any one of the other compounds embraced by formula l is substituted for the particular acrylic acid compound in Examples 3 through 7. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound of the formula CH3 H3 OH 3 M OH H wherein R is cyano or carbalkoxy of 2 to 4 carbon atoms.

2. A compound of claim 1, wherein R is cyano or methoxy.

3. The compound of claim 2 which is 3-(3B- tridigitoxosyl- 1 2'13, 1 4B-dihydroxy-5 'B-androstanl7B-yl)-acrylonitrile 3"',4"'-carbonate.

4. The compound of claim 2 which is methyl 3-(3'B- tridigitoxosyll 2 'B, l 4'B-dihydroxy-5 'fi'androstanl7'fi-yl)-acrylate 3"',4"-carbonate. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1, wherein R is cyano or methoxy.
 3. The compound of claim 2 whicH is 3-(3'' Beta -tridigitoxosyl-12'' Beta ,14'' Beta -dihydroxy-5'' Beta -androstan-17'' Beta -yl)-acrylonitrile 3'''''',4''''''-carbonate.
 4. The compound of claim 2 which is methyl 3-(3'' Beta -tridigitoxosyl-12'' Beta ,14'' Beta -dihydroxy-5'' Beta -androstan-17'' Beta -yl)-acrylate 3'''''',4''''''-carbonate. 